U.S. Pat. No. 5,262,439 to Parthasarathy, which is assigned to AtheroGenics, Inc. discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. The '439 patent reports that carboxylic acid derivatives of probucol can be prepared by treating probucol with an excess of dicarboxylic acid anhydride and catalytic amounts of 4-dimethyl-aminopyridine at a temperature sufficient to ensure that the dicarboxylic acid anhydride is liquid. Under these conditions, no anhydrous solvent is necessary, as the anhydride itself acts as a solvent.
WO 01/70757 filed by AtheroGenics, Inc. describes the use of certain compounds of the following formula, and pharmaceutically acceptable salts thereof along with method of use and methods of manufacturing:
wherein                a) Ra, Rb, Rc, and Rd are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and        b) Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) C1-10alkyl or substituted C1-10alkyl, terminated by sulfonic acid, (iv) C1-10alkyl, or substituted C1-10alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted C1-10alkyl-O—C(O)—C1-10alkyl, (vi) straight chained polyhydroxylated C3-10 alkyl; (vii)-(CR2)1-6—COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii)-(CR2)1-6—X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.        
U.S. Pat. No. 6,147,250, assigned to AtheroGenics, Inc., provides compounds, compositions, method for inhibiting the expression of VCAM-1, and methods of preparing said compounds and compositions. The patent reports that a monoester can be prepared by treating a quantity of probucol in a 0.1 M solution of tetrahydrofuran with 2 equivalents of sodium hydride and stirred at room temperature for 30 minutes. To the reaction mixture is added 3 equivalents of an acid chloride or acid anhydride and the reaction stirred at room temperature for 16 hours. The reaction is quenched with 1 N HCl and diluted with ethyl acetate. The aqueous layer is removed and the ethyl acetate layer is washed with water and then with an aqueous saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate, gravity or vacuum filtered, and then concentrated. The product is purified by silica gel chromatography yielding 14% of the desired compound.
U.S. Pat. No. 6,323,359 discloses and claims methods of manufacturing a group of compounds found in the '250 patent. The '359 patent discloses the use of alkali metal hydroxide, alkali metal alkoxide, alkali ammonium alkoxide, alkyl ammonium hydroxide to form alkali metal salts of probucol compounds and then reacting the salts with dicarboxylic acid anhydride.
French Patent Publication No. 2.168.137 describes the production of diesters of probucol by reacting probucol with a halide or anhydride of an organic acid in an inert solvent with heat and in the presence of a base such as an alkaline hydroxide or carbonate, a tertiary amine or a tertiary nitrogenous heterocycle. The O-metallic derivative of probucol can also be used as the reaction intermediate.
What is still needed is a method of manufacturing a group of compounds described in U.S. Pat. Nos. 6,141,250; 6,323,359; 5,262,439; and WO 01/70757 that is efficient and gives good yields.
It is another object of the invention to provide a process for the preparation of monoesters and monoethers of probucol or a probucol derivative that optimizes the amount of final product.
It is yet another object of the present invention to provide a process for the preparation of monoesters and monoethers of probucol or a probucol derivative that minimizes the amount of reagent used.